Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells

Pritha S. Nayak, Yulian Wang, Tanbir Najrana, Lauren M. Priolo, Mayra Rios, Sunil K. Shaw, Juan Sanchez-Esteban

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Mechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury. Methods: Expression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively. Results: TRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4. Conclusion: These studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.

Original languageEnglish (US)
Article number60
JournalRespiratory Research
Volume16
Issue number1
DOIs
StatePublished - May 27 2015

Fingerprint

TRPV Cation Channels
Epithelial Cells
Inflammation
Lung
Lung Injury
Interleukin-6
Cellular Mechanotransduction
Epithelium
Ventilator-Induced Lung Injury
Pregnancy
Mechanoreceptors
MAP Kinase Signaling System
Acute Lung Injury
Artificial Respiration
Western Blotting
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Cytokines
Calcium

Keywords

  • Differentiation
  • Fetal epithelial cells
  • Inflammation
  • Lung
  • Mechanotransduction
  • TRPV4

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells. / Nayak, Pritha S.; Wang, Yulian; Najrana, Tanbir; Priolo, Lauren M.; Rios, Mayra; Shaw, Sunil K.; Sanchez-Esteban, Juan.

In: Respiratory Research, Vol. 16, No. 1, 60, 27.05.2015.

Research output: Contribution to journalArticle

Nayak, Pritha S. ; Wang, Yulian ; Najrana, Tanbir ; Priolo, Lauren M. ; Rios, Mayra ; Shaw, Sunil K. ; Sanchez-Esteban, Juan. / Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells. In: Respiratory Research. 2015 ; Vol. 16, No. 1.
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abstract = "Background: Mechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury. Methods: Expression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively. Results: TRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4. Conclusion: These studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.",
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AB - Background: Mechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury. Methods: Expression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively. Results: TRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4. Conclusion: These studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.

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